Process for the preparation of aminoalcohol derivatives and their further conversion to (1R,4S)-4-(2-amino-6-chloro-5-formamido-4-pyrimidinyl)-amino)-2-cyclopentenyl-1-methanol

ABSTRACT

The invention relates to a novel process for the preparation of an aminoalcohol of the formula 
                         
racemically or optically active, starting from 2-azabi-cyclo[2.2.1]hept-5-en-3-one, its further conversion to give the corresponding acyl derivative and its further conversion to (1S,4R)— or (1R,4S)-4-(2-amino-6-chloro-9-H-purine-9-yl)-2-cyclopentenyl-1-methanol of the formulae
 
                         
In the latter synthesis, the aminoalcohol is converted into the corresponding D- or L-tartrate, which is then reacted with N-(2-amino-4,6-dichloropyrimidin-5-yl) formamide of the formula
 
                         
to give (1S, 4R)- or (1R, 4S)-4-[(2-amino-6-chloro-5-formamido-4-pyrimidinyl)amino]-2-cyclopentenyl-1-methanol of the formulae
 
                         
and then cyclized to give the end compounds.

This application is a divisional of U.S. Ser. No. 09/198,427, filed Nov.24, 1998, now U.S. Pat. No. 6,723,868, which is hereby incorporated byreference and claims the benefit of (1) Swiss Patent Application No.2739/97, filed Nov. 27, 1997, (2) Swiss Patent Application No. 2781/97,filed Dec. 3, 1997, (3) Swiss Patent Application No. 0133/98, filed Jan.21, 1998, (4) Swiss Patent Application No. 0723/98, filed Mar. 27, 1998,and (5) European Patent Application No. 98118895.6, filed Oct. 7, 1998.

The present invention relates to a novel process for the preparation of(1R, 4S)— or (1S, 4R)-1-amino-4-(hydroxymethyl)-2-cyclopentene of theformulae

or salts thereof, or the D- or L-hydrogentartrates thereof and alsotheir further conversion to give (1S, 4R)— or (1R,4S)-4-(2-amino-6-chloro-9-H-purine-9-yl)-2-cyclopentene. (1R,4S)-1-Amino-4-(hydroxymethyl)-2-cyclopentene of the formula IV is animportant intermediate for the preparation of carbocyclic nucleosidessuch as, for example, Carbovir® (Campbell et al., J. Org. Chem. 1995,60, 4602–4616).

A process for the preparation of (1R,4S)-1-amino-4-(hydroxymethyl)-2-cyclopentene is described, for example,by Campbell et al. (ibid) and by Park K. H. & Rapoport H. (J. Org. Chem.1994, 59, 394–399). In this process, the starting material is eitherD-glucono-δ-lactone or D-serine, approximately 15 synthesis stages beingrequired to form (1R,4S)-N-tert-butoxy-carbonyl-4-hydroxymethyl-2-cyclopentene, and theprotecting group is removed to give (1R,4S)-1-amino-4-(hydroxy-methyl)-2-cyclopentene.

Both these processes are costly, complex and not practicableindustrially. WO 93/17020 describes a process for the preparation of(1R, 4S)-1-amino-4-(hydroxymethyl)-2-cyclopentene, in which (1R,4S)-4-amino-2-cyclopentene-1-carboxylic acid is reduced to the desiredproduct using lithium aluminium hydride.

Disadvantages of this process are firstly that the double bond of thecyclopentene ring is also reduced, the poor handling properties oflithium aluminium hydride and secondly that it is too costly.

Taylor S. J. et al. (Tetrahetron: Asymmetry Vol. 4, No. 6, 1993,1117–1128) describe a process for the preparation of (1R,4S)-1-amino-4-(hydroxymethyl)-2-cyclopentene starting from(±)-2-azabicyclo[2.2.1]hept-5-en-3-one as starting material. In thisprocess, the starting material is converted, using microorganisms of thespecies Pseudomonas solanacearum or Pseudomonas fluorescens, into (1R,4S)-2-azabicyclo[2.2.1]hept-5-en-3-one, which is then reacted withdi-tert-butyl dicarbonate to give (1R,4S)-N-tert-butoxycarbonyl-2-azabicyclo[2.2.1]hept-5-en-3-one, and thelatter is reduced using sodium borohydride and trifluoroacetic acid togive the desired product. This process is far too costly.In addition, Martinez et al. (J. Org. Chem. 1996, 61, 7963–7966)describe a 10-stage synthesis of (1R,4S)-1-amino-4-(hydroxymethyl)-2-cyclopentene starting from diethyldialkylmalonate. This process too has the disadvantage that it iscomplex and not practicable industrially.It is also known that N-substituted(±)-2-azabicyclo-[2.2.1]hept-5-en-3-ones, which carry anelectron-with-drawing substituent, can be reduced to the correspondingN-substituted aminoalcohols using a metal hydride (Katagiri et al.,Tetrahedron Letters, 1989, 30, 1645–1648; Taylor et al., ibid).

In contrast to this, it is known that unsubstituted(±)-2-azabicyclo[2.2.1]hept-5-en-3-one of the formula

is reduced with lithium aluminium hydride to give(±)-2-azabicyclo[2.2.2]octene (Malpass & Tweedle, J. Chem. Soc., PerkinTrans 1, 1977, 874–884), and that the direct reduction of(±)-2-azabicyclo[2.2.2]hept-5-en-3-one to give the correspondingaminoalcohol has to date been impossible (Katagiri et al., ibid; Tayloret al., ibid).

It is also known to resolve racemic1-amino-4-(hydroxymethyl)-2-cyclopentene using (−)-dibenzoyl-tartaricacid (U.S. Pat. No. 5,034,394). On the one hand, this reaction has thedisadvantage that (−)-dibenzoyltartaric acid is expensive, and, on theother hand, that the separation must take place in the presence of anexactly defined mixture of acetonitrile and ethanol. This solventmixture cannot be removed and must be fed to the combustion.

The object of the present invention was to provide a simple, economicaland cost-effective process for the preparation of a (1R,4S)-1-amino-4-(hydroxy-methyl)-2-cyclopentene.

Surprisingly, it has now been found that when(±)-2-azabicyclo[2.2.1]hept-5-en-3-one of the formula

in the form of the racemate or one of its optically active isomers, isreduced with a metal hydride, the aminoalcohol of the formula

in the form of the racemate or one of its optically active isomers isobtained in a simple manner.

As the person skilled in the art is aware, the aminoalcohol of theformula I can be converted using an acid into the corresponding salts,such as, for example, into hydrohalide salts. Suitable hydrohalide saltsare hydrobromides and hydrochlorides.

The starting material, the (±)-2-azabicyclo-[2.2.1]hept-5-en-3-one canbe prepared according to EP-A 0 508 352.

Metal hydrides which may be used are alkali metal or alkaline earthmetal hydrides and also binary or complex metal hydrides of the boron oraluminium group, such as alkali metal and alkaline earth metalboro-hydrides, alkali metal and alkaline earth metal aluminium hydrides.Suitable alkali metal or alkaline earth metal hydrides are LiH, NaH, KH,BeH₂, MgH₂ or CaH₂.

Binary alkali metal or alkaline earth metal borohydrides which may beused are NaBH₄, LiBH₄, KBH₄, NaAlH₄, LiAlH4, KAlH₄, Mg(BH₄)₂, Ca(BH₄)₂,Mg(AlH₄)₂ and Ca(AlH₄)₂. Complex metal hydrides of the boron oraluminium group may have the general formula M¹M²H_(n)L_(m), in which nis an integer from 1 to 4, and m is an integer from 4 to 4 minus thecorresponding number n, M¹ is an alkali metal atom, M² is boron oraluminium, and L is C₁₋₄-alkyl, C₁₋₄-alkenyl, C₁₋₄-alkoxy, CN or anamine, or the complex metal hydrides may have the general formulaM²H_(O)L_(p), in which M² is as defined above and O is an integer from 0to 3, and p is an integer from 3 to 3 minus the corresponding number p.Possible M¹M²H_(n)L_(m) compounds are LiBH (C₂H₅)₃, LiBHX(OCH₃)_(4-x),LiAlH (OC(CH₃)₃)₃, NaAlH₂ (OC₂H₄OCH₃)₂, NaAlH₂ (C₂H₅)₂ or NaBH₃CN.Preferably, the reduction is carried out using a metal borohydride. Asan expert in the art is aware, the metal hydrides mentioned such as, forexample, LiBH₄, can also be produced “in situ”. Common preparationmethods for LiBH₄ are, for example, the reaction of an alkali metalboro-hydride with a lithium halide (H. C. Brown et al., Inorg. Chem. 20,1981, 4456–4457), the reaction of LiH with B₂O₃ in the presence ofhydrogen and a hydrogenation catalyst (EP-A 0 512 895), the reaction ofLiH with (H₅C₂)OBF₃ (DE-A 94 77 02) and that of LiH with B(OCH₃)₃ (U.S.Pat. No. 2,534,533).

The metal hydrides are expediently used in a molar ratio of from 1 to 5per mole of (±)-2-azabicyclo-[2.2.1]hept-5-en-3-one.

The metal hydrides, in particular NaBH₄, are preferably used withlithium salt additives. Lithium salts which may be used are LiCl, LiF,LiBr, LiI, Li₂SO₄, LiHSO₄, Li₂CO₃, Li(OCH₃) and LiCO₃.

The reduction is expediently carried out in an inert-gas atmosphere,such as, for example, in an argon or nitrogen atmosphere.

The reduction can be carried out at a temperature of from −20 to 200°C., preferably at a temperature of from 60 to 150° C.

Suitable solvents are aprotic or protic organic solvents. Suitableaprotic organic solvents may be ethers or glycol ethers, such as, forexample, diethyl ether, dibutyl ether, ethyl methyl ether, diisopropylether, tert-butyl methyl ether, anisole, dioxane, tetrahydrofuran,monoglyme, diglyme and formaldehyde dimethyl-acetal. Suitable proticorganic solvents are C₁₋₆-alcohols, such as methanol, ethanol, propanol,isopropanol, butanol, tert-butanol, pentanol, tert-amyl alcohol orhexanol and also mixtures of these with water. Suitable protic organicsolvents are also mixtures of one of said ethers, glycol ether withwater or with one of said alcohols, such as a mixture of a C₁₋₆-alcoholwith an ether or glycol ether, in particular a mixture of methanol,ethanol or water with diethyl ether, tetrahydro-furan, dioxane, glyme ordiglyme. The solvent used is preferably a protic organic one, such as amixture of a C₁₋₆-alcohol or water with an ether or glycol ether.

In a preferred embodiment, the reduction is carried out in the presenceof an additive, such as in the presence of water or of a lower aliphaticalcohol. The lower aliphatic alcohol may be methanol, ethanol,methoxyethanol, n-propanol, isopropanol, isobutanol, tert-butanol,n-butanol, diols such as butanediol, and triols such as glycerol. Inparticular, the lower aliphatic alcohol is methanol or ethanol. Here,the lower aliphatic alcohol is expediently used in a molar ratio of from2 to 15 per mol of (±)-2-azabicyclo[2.2.1]hept-5-en-3-one.

If the reaction is carried out in the presence of said alcohol, thecorresponding amino acid ester can be formed in situ (intermediate).I.e. if the starting material used is(±)-2-azabicyclo[2.2.1]hept-5-en-3-one, according to the invention thecorresponding (±)-amino acid ester can be formed. If the startingmaterial used is (−)-2-azabicyclo[2.2.1]hept-5-en-3-one, according tothe invention the (−)-amino acid ester can correspondingly be formed asintermediate.

Surprisingly, it has also been found that when a cyclopentene derivativeof the general formula

in the form of the racemate or one of its optically active isomers, inwhich R is C₁₋₄-alkyl, C₁₋₄-alkoxy, aryl or aryloxy, is hydrolyzed withan alkali metal hydroxide, the aminoalcohol of the formula

in the form of the racemate or one of its optically active isomers isobtained in a simple manner.

C₁₋₄-Alkyl can be substituted or unsubstituted. In the text belowsubstituted C₁₋₄-alkyl is taken to mean C₁₋₄-alkyl substituted by ahalogen atom. The halogen atom may be F, Cl, Br or I. Examples ofC₁₋₄-alkyl are methyl, ethyl, propyl, butyl, isobutyl, tert-butyl,isopropyl, chloromethyl, bromomethyl, dichloromethyl and dibromo-methyl.The C₁₋₄-alkyl is preferably methyl, ethyl, propyl, butyl, isobutyl orchloromethyl.

The C₁₋₄-alkoxy used may be, for example, methoxy, ethoxy, propoxy orbutoxy. The aryl used can be, for example, phenyl or benzyl, substitutedor unsubstituted. The aryloxy used can be, for example, benzyloxy orphenoxy, substituted or unsubstituted.

The alkali metal hydroxide used may be sodium or potassium hydroxide.

For this process variant, the cyclopentene derivative of the generalformula III is preferably prepared by reduction of the correspondingacyl-2-aza-bicyclo[2.2.1]hept-5-en-3-one of the general formula

in the form of the racemate or one of its optically active isomers, inwhich R is as defined above, using one of the metal hydrides alreadymentioned in an anhydrous solvent.

The anhydrous solvent may be protic or aprotic organic solvents, inparticular an anhydrous protic organic solvent such as a tertiaryalcohol. The tertiary alcohol may be tert-butyl alcohol or tert-amylalcohol.

As already mentioned above, this reduction is also preferably carriedout in the presence of an addition, such as in the presence of a loweraliphatic alcohol such as methanol, in particular in the presence of 2mol of methanol per mole of acyl-2-azabicyclo-[2.2.1]hept-5-en-3-one(formula IV).

The reaction is expediently carried out at a temperature of from 0 to50° C., preferably from 15 to 30° C.

The racemic aminoalcohol of the formula I is then converted according tothe invention either by chemical means using an optically activetartaric acid or by biotechnological means using a hydrolase in thepresence of an acylating agent to give (1R, 4S)— or (1S,4R)-1-amino-4-(hydroxymethyl)-2-cyclopentene of the formula

or salts thereof and/or to give (1S, 4R)— or (1R,4S)-1-amino-4-(hydroxymethyl)-2-cyclopentene derivative of the generalformulae

or salts thereof, in which X and Y are identical or different and are anacyl group or H, with the exception of X=Y=H.

The hydrolases used may be lipases, proteases, amidases or esterases,lipases being expediently used.

In the text below, salts are taken to mean hydrohalide salts such ashydrochlorides, hydrobromides or tartrates.

As the person skilled in the art is aware, hydrolase-catalyzedacylations in which optically active compounds are formed are carriedout in the presence of a suitable acylating agent (Balkenhohl et al.,1997, J. Prakt. Chem. 339, 381–384; K. Faber, “Biotransformation inOrganic Chemistry”, 2nd ed., Berlin 1995, 270–305). Suitable acylatingagents are generally carboxylic acid derivatives such as carboxamides,carboxylic anhydrides or carboxylic esters. The carboxylic esters may,for example, be alkoxycarboxylic esters, such as ethyl methoxyacetateand isopropyl methoxyacetate, C₁₋₆-carboxylic esters, such as butylacetate, ethyl butyrate and ethyl hexanoate, glyceryl esters, such astributyrin (glyceryl tributyrate), glycol esters, such as glycoldibutyrate and diethyl diglycolate, dicarboxylic esters, such as diethylfumarate and malonate, cyanocarboxylic esters, such as ethylcyanoacetate, or cyclic esters, such as, for example, 6-caprolactone.

Accordingly, the acyl group in the formulae VII and VIII corresponds tothe acid component of the carboxylic acid derivative used.

The lipases used may be standard commercial lipases, such as, forexample: Novo lipase SP523 from Aspergillus oryzae (Novozym 398), Novolipase SP524 from Aspergillus oryzae (lipase=Palatase 20000 L fromNovo), Novo lipase SP525 from Candida antarctica (lipase B Novozym 435,immobilized), Novo lipase SP526 from Candida antarctica (lipaseA=Novozym 735, immobilized), lipase kits from Fluka (1 & 2), Amano Plipase, lipase from Pseudomonas sp., lipase from Candida cylindracea,lipase from Candida lypolytica, lipase from Mucor miehei, lipase fromAspergillus niger, lipase from Bacillus thermocatenulatus, lipase fromCandida antarctica, lipase AH (Amano; immobilized), lipase P (Nagase),lipase AY from Candida rugosa, lipase G (Amano 50), lipase F (AmanoF-AP15), lipase PS (Amano), lipase AH (Amano), lipase D (Amano), lipaseAK from Pseudomonas fluorescens, lipase PS from Pseudomonas cepacia,newlase I from Rhizopus niveus, lipase PS-CI (immobilized lipase fromPseudomonas cepacia). These lipases may, as the person skilled in theart is aware, be used as cell-free enzyme extracts or else in thecorresponding microorganism cell.

The proteases may also be commercially available, such as, for example,serine proteases such as subtilisins. The subtilisin may be savinasefrom Bacillus sp., alcalase, subtilisin from Bacillus licheniformis andalso proteases from Aspergillus, Rhizopus, Streptomyces or Bacillus sp.

The biotechnological racemate resolution is expediently carried out at atemperature of from 10 to 80° C. and at a pH of from 4 to 9.

The biotechnological racemate resolution is expediently carried out in aprotic or aprotic organic solvent. Suitable aprotic organic solvents areethers such as tert-butyl methyl ether, diisopropyl ether, dibutylether, dioxane and tetrahydrofuran, aliphatic hydrocarbons such ashexane, organic bases such as pyridine, and carboxylic esters such asethyl acetate, and suitable protic organic solvents are theC₁₋₆-alcohols already described, such as, for example, pentanol.

The (1S, 4R)— or (1R, 4S)-1-amino-4-(hydroxy-methyl)-2-cyclopentenederivatives of the general formulae VII and VIII formed in accordancewith the invention during the biotechnological racemate resolution are,depending on the desired target compound (aminoalcohol of the formula Vor VI), hydrolyzed by chemical means to give the aminoalcohol of theformula V or VI. The chemical hydrolysis is expediently carried out inan aqueous basic solution or using a basic ion exchanger. The aqueousbasic solution is preferably, as for the hydrolysis of the cyclopentenederivatives of the general formula III described above, an alkali metalhydroxide. The basic ion exchangers can, for example, be Dowex 1×8(OH⁻)and Duolite A147.

The chemical racemate resolution is carried out using an opticallyactive tartaric acid such as using D-(−)-tartaric acid or L-(+)-tartaricacid.

The racemate resolution with D-(−)-tartaric acid is expediently carriedout by firstly reacting the racemic1-amino-4-(hydroxymethyl)-2-cyclopentene with the D-(−)-tartaric acid inthe presence of a lower aliphatic alcohol.

Suitable lower aliphatic alcohols are the same as those described above.Preference is given to using methanol. The reaction which leads toformation of the salt is usually carried out at temperature between 20°C. and the reflux temperature of the solvent, preferably at the refluxtemperature.If desired, the 1-amino-4-(hydroxymethyl)-2-cyclopentene D-tartrateformed during the reaction can be further purified by recrystallizationfrom a lower aliphatic alcohol such as methanol.

The racemate resolution with L-(+)-tartaric acid is expediently carriedout as that with D-(−)-tartaric acid. I.e. the racemate resoluton withL-(+)-tartaric acid is likewise carried out in the presence of a loweraliphatic alcohol and at a temperature between 20° C. and the refluxtemperature of the solvent, preferably at the reflux temperature. Aftercooling, the (1S, 4R)-1-amino-4-(hydroxymethyl)-2-cyclopenteneL-hydrogentartrate crystallizes out.

The (1R, 4S)-1-amino-4-(hydroxymethyl)-2-cyclopentene L-hydrogentartrateis present, in particular, in dissolved form in the mother liquor.

Isolation, further purification (liberation) and conversion to thecorresponding salt of (1R, 4S)— or (1S,4R)-1-amino-4-(hydroxymethyl)-2-cyclopentene takes place with a base andsubsequent acid treatment. Suitable bases are alkali metal alkoxides,alkali metal or alkaline earth metal carbonates, or alkali metal oralkaline earth metal hydroxides. The alkali metal alkoxides may besodium or potassium alkoxides. The alkali metal carbonate may bepotassium or sodium carbonate, potassium or sodium hydrogencarbonate,and the alkaline earth metal carbonate may be magnesium or calciumcarbonate. The alkali metal hydroxide may be sodium or potassiumhydroxide, and the alkaline earth metal hydroxide may be calciumhydroxide. Conversion to the corresponding salt usually takes place witha mineral acid such as with sulphuric acid, hydrochloric acid orphosphoric acid, preferably with hydrochloric acid.

(1R, 4S)— or (1S, 4R)-1-amino-4-(hydroxymethyl)-2-cyclopenteneD-hydrogentartrate and (1R, 4S)— or (1S,4R)-1-amino-4-(hydroxymethyl)-2-cyclopentene L-hydrogen-tartrate arecompounds unknown in the literature and are likewise provided by theinvention.

Preference is given to carrying out the chemical racemate resolutionwith D-(+)-tartaric acid due to the higher performance, technicalfacility and more efficient racemate resolution.

As for the racemic aminoalcohol, it is of course also possible to reactthe optically active (1R, 4S)— or (1S,4R)-1-amino-4-(hydroxymethyl)-2-cyclopentenes with D-(−)- orL-(+)-tartaric acid to give the corresponding tartrates.

A further constituent of the present invention is the furtherconversion, the acylation, of the (1R, 4S)— or (1S,4R)-1-amino-4-(hydroxymethyl)-2-cyclopentenes to give the (1R,4S)-1-amino-4-(hydroxymethyl)-2-cyclopentene derivative of the generalformula

Here, the substituent R is as defined in the cyclopenten derivative ofthe general formula III.

The acylation can be carried out using a carbonyl halide of the generalformula

in which X is a halogen atom, and R is as defined above, or using acarboxylic anhydride of the general formula

in which R is as defined above.The halogen atom X may be F, Cl, Br or I. Preference is given to Cl orF.

Examples of carbonyl halides are: acetyl chloride, chloroacetylchloride, butyryl chloride, isobutyryl chloride, phenylacetyl chloride,benzyl chloroformate, propionyl chloride, benzoyl chloride, alkylchloroformate or tert-butyloxycarbonyl fluoride.

Examples of carboxylic anhydrides are: tert-butoxycarbonyl anhydride,butyric anhydride, acetic anhydride or propionic anhydride. Theacylation is preferably carried out using a carboxylic anhydride, inparticular using tert-butoxycarbonyl anhydride.

The acylation can be carried out without solvent or using an aproticorganic solvent. The acylation is expediently carried out in an aproticorganic solvent. Suitable aprotic organic solvents are, for example,pyridine, acetonitrile, dimethylformamide, diisopropyl ether,tetrahydrofuran, toluene, methylene chloride, N-methylpyrrolidone,triethylamine, chloroform, ethyl acetate, acetic anhydride and mixturesthereof.

The acylation is expediently carried out at a temperature of from −20 to100° C., preferably from 0 to 80° C.

The further conversion according to the invention of (1R, 4S)— or (1S,4R)-1-amino-4-(hydroxymethyl)-2-cyclopentene D- or L-hydrogentartrate to(1S, 4R)— or (1R,4S)-4-(2-amino-6-chloro-9-H-purine-9-yl)-2-cyclopentenyl-1-methanol, ora salt thereof, of the formulae

is carried out by reacting (1R, 4S)— or (1S,4R)-1-amino-4-(hydroxymethyl)-2-cyclopentene D- or L-hydrogentartratewith N-(2-amino-4,6-dichloropyrimidin-5-yl)formamide of the formula

to give (1S, 4R)— or (1R,4S)-4-[(2-amino-6-chloro-5-formamido-4-pyrimidinyl)amino]-2-cyclopentenyl-1-methanol of the formulae

and then cyclizing the latter in a known manner to give the compoundsaccording to formula VIII and IX.

N-(2-Amino-4,6-dichloropyrimidin-5-yl) formamide can be preparedaccording to WO 95/21 161.

The reaction is expediently carried out in the presence of a base.Suitable bases are the same as those previously described for liberating(1R, 4S)— or (1S, 4R)-1-amino-4-(hydroxymethyl)-2-cyclopentenes from thecorresponding tartrate.

The reaction is expediently carried out in a protic solvent. The proticsolvent may be lower aliphatic alcohols such as methanol, ethanol,propanol, isopropanol, butanol or isobutanol.

The (1S, 4R)— or (1R,4S)-4-[(2-amino-6-chloro-5-formamido-4-pyrimidinyl)amino]-2-cyclopentenyl-1-methanolof the formula XI or XII is then cyclized in a known manner according toWO 95/21 161 to give the end product according to Formula VIII or IX.

The cyclization is usually carried out dissolved in trialkylorthoformate in the presence of a concentrated aqueous acid. Thetrialkyl orthoformates used may be, for example, trimethyl or triethylorthoformate.

The aqueous acid may be, for example, hydrogen fluoride, sulphuric acidor methanesulphonic acid.

A further constituent of the invention is the overall process for thepreparation of (1S,4R)-4-(2-amino-6-chloro-9-H-purine-9-yl)-2-cyclopentenyl-1-methanol, orsalts thereof, of the formula XII starting from(−)-2-azabicyclo[2.2.1]hept-5-en-3-one or(−)-acyl-2-azabicyclo[2.2.1]hept-5-en-3-one of the formulae

in which R is as defined above, by reduction with a metal hydride togive an aminoalcohol of the formula

or to give a cyclopentene derivative of the general formula

in which R is as defined above, which are then converted into thecorresponding hydrohalide salts, and then reacted withN-(2-amino-4,6-dichloropyrimidin-5-yl)-formamide of the formula

to give (1S,4R)-4-[(2-amino-6-chloro-5-formamido-4-pyrimidinyl)amino]-2-cyclopentenyl-1-methanolof the formula

and then the latter is cyclized in a known manner to give the compoundof the formula

This process variant has the advantage that the hydrohalide salts formedtherein may be used as a crude mixture in the preparation of the productof the formula XII.

EXAMPLES Example 1 Reduction of acyl- orunsubstituted-2-azabicyclo[2.2.1]-hept-5-en-3-one 1.1. Preparation of(±)-acetyl-1-amino-4-(hydroxymethyl)-2-cyclopentene in an AnhydrousProtic Organic Solvent Using Sodium Borohydride

-   -   280 g of 2-methyl-2-butanol (amyl alcohol) and 15.2 g of sodium        borohydride (0.4 mol) were charged into a sulphonation flask at        20° C. A mixture of 907 g of        (±)-acetyl-2-azabicyclo[2.2.1]hept-5-en-3-one (0.6 mol) and 37.5        g of methanol (2 equivalents based on        (±)-acetyl-2-azabicyclo[2.2.1]hept-5-en-3-one was metered into        this suspension over the course of 2 h at 20° C. The reaction        mixture was then stirred for a further 3 h at 20° C. The solvent        was distilled as far as possible (40° C.). Boron was removed by        adding 280 g of methanol and 27.2 g of formic acid, warming the        mixture to 25–30° C. and distilling off the methyl        borate/methanol azeotrope at this temperature (130 to 80 mbar).        The precipitated sodium formate was filtered off, and the        filtrate was reduced by evaporation to give 93.4 g of crude        product as a clear viscous oil; crude yield: about 84–85%.

1.2. Preparation of cis-1-amino-4-(hydroxymethyl)-2-cyclopentene

-   -   A suspension of (±)-2-azabicyclo[2.2.1]hept-5-en-3-one (10.00 g,        91.6 mmol) and lithium borohydride (4.00 g, 183.7 mmol) in dry        dioxane (100 ml) was heated in an inert-gas atmosphere (argon)        for 4 h at 110° C. below the reflux temperature. After this        time, about 20–25% of the starting material had reacted to give        the product (GC analysis with internal standard benzophenone        after work-up of the reaction mixture; work-up: 0.05 ml of the        reaction mixture were quenched with 0.1 ml of 1M HCl and        immediately rendered basic using 0.2 ml of 1M NaOH).    -   The structural detection of the product was carried out by        H-NMR, GC and GC-MS.

1.3. Preparation of (+)-1-amino-4-(hydroxymethyl)-2-cyclopentene

-   -   A 25 ml round-bottom flask was charged with 1.0 g (9.2 mmol) of        (+)-2-azabicyclo[2.2.1]hept-5-en-3-one and 0.4 g (18.4 mmol) of        lithium borohydride, under an inert-gas atmosphere, in 10 ml of        dioxane, and the mixture was refluxed for 3 h at 110° C. Excess        reducing agent was destroyed by adding about 5 ml of        semi-concentrated HCl (adjusted to pH 3). The mixture was then        immediately buffered by adding about 1 ml of saturated NaHCO₃        solution at pH 8. GC analysis indicated the formation of the        product. The entire reaction mixture was then evaporated to        dryness and purified by means of column chromatography        (gradient: hexane/ethyl acetate/MeOH=1:1:1−> MeOH). In this way        (+)-2-azabicyclo-[2.2.1]hept-5-en-3-one and the corresponding        (+)-aminoalcohol were obtained.

1.4. Preparation of (−)-1-amino-4-(hydroxymethyl)-2-cyclopentene

-   -   A 25 ml round-bottom flask was charged with 1.0 g (9.2 mmol) of        (−)-2-azabicyclo[2.2.1]hept-5-en-3-one and 0.4 g (18.4 mmol) of        lithium borohydride, under an inert-gas atmosphere, in 10 ml of        dioxane, and the mixture was refluxed for 3 h at 110° C. Excess        reducing agent was destroyed by adding about 5 ml of        semi-concentrated HCl (adjusted to pH 3). The mixture was then        immediately buffered by adding about 1 ml of saturated NaHCO₃        solution at pH 8. GC analysis indicated the formation of the        product in 18% yield (GC standard is benzophenone). The entire        reaction mixture was then evaporated to dryness and purified by        means of column chromatography (gradient: hexane/ethyl        acetate/MeOH=1:1:1−> MeOH). In this way, 0.43 g (43%) of        (−)-2-azabicyclo[2.2.1]-hept-5-en-3-one was reisolated and 0.04        g (4%) of the corresponding (−)-aminoalcohol was obtained.    -   By HPLC, only the (−)-enantiomer of the aminoalcohol was        detectable. The ee of the product is thus >98%.

1.5. Preparation of (±)-1-amino-4-(hydroxymethyl)-2-cyclopentene in anAlcohol

-   -   A 100 ml round-bottom flask fitted with magnetic stirrer was        charged with 3.0 g (27.5 mmol) of        (±)-2-azabicyclo[2.2.1]hept-5-en-3-one and 1.2 g (28.3 mmol) of        lithium borohydride, under an inert-gas atmosphere, in 35 g of        2-butanol, and the mixture was stirred for 3 h at 60° C. GC        analysis of a sample (work-up: 0.1 g sample rendered acidic        using 0.2 ml of 1M HCl, then quickly rendered basic using 0.1 ml        of saturated NaHCO₃) indicated the formation of the product in        12% yield after this time. (GC standard is benzophenone.)

1.6. Preparation of a (±)-1-amino-4-(hydroxymethyl)-2-cyclopentene in anAlcohol/Ether Mixture

-   -   A 10 ml round-bottom flask was charged under at inert-gas        atmosphere with 0.5 g (4.6 mmol) of        (±)-2-azabicyclo[2.2.1]hept-5-en-3-one and 0.59 g (18.4 mmol) of        methanol in 7.5 ml of dioxane (abs.). 0.21 g (9.2 mmol) of        lithium borohydride were added, and the mixture was heated for 4        h at 60° C. The mixture was then cooled to 5° C. using an        ice/waterbath, and about 10 ml of semi-concentrated HCl was        carefully added to the reaction mixture (vigorous reaction, gas        evolution), as a result of which a yellowish clear solution        formed. This solution was analyzed directly by a quantitative        ion-chromatographic method. It contained 0.60 mmol (13.1%) of        (±)-2-azabicyclo[2.2.1]hept-5-en-3-one (determined as HCl salt        of the corresponding amino acid, which is the acidic hydrolysis        product of (±)-2-azabicyclo-[2.2.1]hept-5-en-3-one) and 3.06        mmol of product, corresponding to a yield of 66.8%,        aminoalcohol.

1.7. Preparation of (±)-1-amino-4-(hydroxymethyl)-2-cyclopentene in thePresence of Additives Such as Water or Various Alcohols

-   -   A 10 ml round-bottom flask was charged with 0.50 g (4.66 mmol)        of (±)-2-azabicyclo[2.2.1)hept-5-en-3-one and 0.30 g (13.7 mmol)        of lithium borohydride in 7.5 ml of abs. dioxane, and the        mixture was heated to 60° C.    -   At this temperature, over the course of 30 min, X mmol of        alcohol Y was added dropwise using a syringe. The mixture is        then stirred for 2 h at 60° C., cooled to about 20° C. and        poured into about 10 ml of semi-concentrated HCl. The content        was then determined directly using a quantitative        ion-chromatographic method (cf. Table 1).

TABLE 1 (±)-2-Azabicyclo- [2.2.1]- X hept-5-en- Amino- equiv- 3-onealcohol Example Additive Y X mmol alents % yield 1.7.1 — — — 15 52 1.7.2water 17.1 1.25 23.3 67.5 1.7.3 water 34.3 2.5 32.3 58.3 1.7.4 methanol34.3 2.5 4.5 83.1 1.7.5 ethanol 34.3 2.5 6.5 74.7 1.7.6 isopropanol 34.32.5 28.1 52.3

1.8. Preparation of (±)-1-amino-4-(hydroxymethyl)-2-cyclopentene withVarious Amounts of Methanol

-   -   Using the procedure of Example 1.7, the reaction was carried out        in a variety of methanol concentrations. The results are given        in Table 2.

TABLE 2 (±)-2-Azabicyclo [2.2.1]- hept-5-en-3- Methanol Methanol oneAminoalcohol Example mmol equivalents % yield 1.8.1 9.2 1 27.5 44.81.8.2 18.3 2 13.1 66.8 1.8.3 27.5 3 24.7 54.8 1.8.4 36.6 4 5.7 56.81.8.5 45.8 5 12.0 58.3 1.8.6 55.0 6 7.2 33.0

1.9 Preparation of (±)-1-amino-4-(hydroxymethyl)-2-cyclopentene withVarious Solvents

-   -   Using the procedure of Example 1.7, the reaction was carried out        in a variety of solvents (7.5 ml) and the content was        determined. The results are given in Table 3.

TABLE 3 (±)-2-Azabicyclo- [2.2.1]- hept-5- en-3-one Aminoalcohol ExampleSolvent X % Yield 1.9.1 dioxane 13.6 79.8 1.9.2 diethyl ether 10.8 68.61.9.3 tetrahydrofuran 22.4 67.6 1.9.4 diisopropyl ether 12.6 51.3 1.9.5tert-butyl methyl 10.0 71.3 ether 1.9.6 monoglyme 15.5 75.3 1.9.7formaldehyde 12.0 74.2 dimethyl acetal

1.10 Preparation of (±)-1-amino-4-(hydroxymethyl)-2-cyclopentene withVarious Additions of LiBH₄

-   -   Following the procedure of Example 1.7, the reaction was carried        out using a variety of LiBH₄ concentrations, and the content was        determined. The results are given in Table 4.

TABLE 4 (±)-2-Azabicyclo- [2.2.1]- hept-5-en- LiBH₄ LiBH₄ 3-oneAminoalcohol Example mmol equivalents % yield 1.10.1 4.6 1 11.9 47.91.10.2 6.9 1.5 9.6 45.6 1.10.3 9.2 2 12.7 71.3 1.10.4 11.5 2.5 13.3 74.51.10.5 13.8 3 12.8 77.1 1.10.6 16.1 3.5 12.7 62.4

1.11 Preparation (1R, 4S)— and (1S,4R)-1-amino-4-(hydroxymethyl)-2-cyclopentene in the Presence of VariousAlcohols and in the Presence of Water in a Variety of Solvents

-   -   A 10 ml round-bottom flask fitted with magnetic stirrer was        charged with 0.50 g (4.6 mmol) of        (±)-2-azabicyclo[2.2.1]hept-5-en-3-one and 0.30 g (13.7 mmol) of        lithium borohydride in 6 ml of a variety of solvents, and the        mixture was heated to 60° C. At this temperature, over the        course of 30 min, 34.3 mmol of the additive Y were added        dropwise using a syringe. The mixture was then stirred for 2 h        at 60° C., cooled to about 20° C. and poured onto about 10 ml of        semi-condentrated HCl.    -   The content is determined directly using a quantitative        ion-chromatographic method (cf. Table 5). The ee value of the        product was determined by means of HPLC. The results are given        Table 5.

TABLE 5 (−)-2-Azabicyclo- [2.2.1]hept- (+)-2-Azabicyclo- 5-en-3-one[2.2.1]hept- Aminoalcohol Example ee value 5-en-3-one Solvent Additive YYield (IC) ee value (HPLC) 1 98.0 dioxane water 64.3 >99.0 2 98.0 glymewater 68.0 >99.0 3 75.9 dioxane water 65.1 76.0 4 75.9 glyme water 63.575.6 5 50.2 dioxane water 74.8 51.4 6 51.6 glyme water 64.1 53.0 7 25.3dioxane water 61.1 30.4 8 25.6 glyme water 61.0 29.6 9 98.0 dioxanemethanol 83.1 98.2 10 98.0 glyme methanol 81.5 99.2 11 75.9 dioxanemethanol 81.4 78.0 12 76.2 glyme methanol 79.9 78.6 13 50.4 dioxanemethanol 81.3 54.4 14 51.5 glyme methanol 82.0 55.2 15 24.8 dioxanemethanol 65.2 27.4 16 27.8 glyme methanol 81.7 32.2 17 98.0 dioxaneethanol 80.8 80.8 18 98.0 glyme ethanol 85.1 85.1 19 75.5 dioxaneethanol 85.3 78.2 20 75.6 glyme ethanol 83.6 78.4 21 50.7 dioxaneethanol 76.3 54.4 22 51.1 glyme ethanol 71.3 55.2 23 25.4 dioxaneethanol 73.0 28.6 24 25.5 glyme ethanol 75.0 28.6 25 98.0 dioxane water62.0 >99.0 26 98.0 glyme water 59.5 >99.0 27 51.3 dioxane water 79.052.2 28 49.0 glyme water 61.3 52.0 29 98.0 dioxane methanol 77.2 >99.030 98.0 glyme methanol 80.0 >99.0 31 49.0 dioxane methanol 80.8 46.8 3249.5 glyme methanol 80.9 48.8

1.12 Preparation of (±)-1-amino-4-(hydroxymethyl)-2-cyclopentene UsingSodium Borohydride in Various Alcohols

-   -   Following the procedure of Example 1.7, the reaction was carried        out in a variety of alcohols. In contrast to Example 1.7,        however, sodium borohydride (0.51 g, 13.7 mmol) was used as        reducing agent. The results are given in Table 6.

TABLE 6 (±)-2-Azabicyclo- [2.2.1]- hept-5- Amino- Additive X X en-3-onealcohol Example Y mmol equivalents Yield % y 1.12.1 water 17.1 1.25 75.420.1 1.12.2 water 34.3 2.5 71.9 26.7 1.12.3 methanol 34.3 2.5 39.2 22.21.12.4 ethanol 34.3 2.5 67.8 8.6 1.12.5 — — — 62.2 3.5

1.13 Preparation of (±)-1-amino-4-(hydroxymethyl)-2-cyclopentene UsingNaBH₃CN

-   -   60 ml of dioxane and 8.6 g (137 mmol) of sodium cyanoborohydride        and 11.9 g (137 mmol) of lithium bromide were refluxed overnight        for 15 h at 110° C. in a 100 ml sulphonation flask. The mixture        was then cooled to 60° C., and a solution of 5.0 g (45.8 mmol)        of (±)-2-azabicyclo[2.2.1]hept-5-en-3-one containing 15 ml of        methanol were added dropwise over the course of 30 min. The        white suspension was stirred for 3 h at 60° C., cooled to about        5° C. and poured into about 100 ml of semi-concentrated HCl. The        content was then determined directly using a quantitative        ion-chromatographic method. The yield of aminoalcohol was about        4%.

Example 2 Alkaline Hydrolysis ofAcetyl-(±)-1-amino-4-(hydroxymethyl)-2-cyclopentene

-   -   88.9 g of racemic        acetyl-1-amino-4-(hydroxymethyl)-2-cyclopentene (content 77.2%)        were suspended (partially dissolved) in 70 g of water. 84 g of        30% NaOH (1.1 equivalents) were added thereto, and the solution        was refluxed for 3 h. According to TLC, the hydrolysis was        complete. The resulting acetate was removed by electrodialysis.        The obtained aqueous solution was reduced by evaporation and        dried by azeotropic distillation with butanol. The residue was        taken up in methanol for racemate resolution. Yield of        hydrolysis to (±)-1-amino-4-(hydroxymethyl)-2-cyclopentene was        90%.

Example 3 Preparation of (1R, 4S)— or (1S,4R)-1-amino-4-(hydroxymethyl)-2-cyclopentene 3.1 Racemate ResolutionUsing Hydrolases 3.1.1 Preparation of (1R,4S)-1-amino-4-(hydroxymethyl)-2-cyclopentene Using Lipases

-   3.1.1.1 25 mM of racemic 1-amino-4-(hydroxymethyl)-2-cyclopentene    were suspended with 1000 units of Novozym 435 in 5 ml of dioxane at    room temperature. 25 mM of ethyl methoxyacetate were added as    acetylating agent. The formation of N-methoxyacetylaminoalcohol was    unambiguously detected by TLC. The conversion was 50% (according to    estimation of the TLC). This reaction produced (1R,    4S)-1-amino-4-(hydroxy-methyl)-2-cyclopentene.-   3.1.1.2 50 mM of racemic 1-amino-4-(hydroxymethyl)-2-cyclopentene    were suspended with 1000 units (U) of Novozym 435 in 5 ml of    tetrahydrofuran. 50 mM of NaOH and 50 mM of ethyl methoxyacetate    were added, and the mixture was incubated at 30° C.    N-Methoxyacetylaminoalcohol was detected using TLC. The estimated    conversion was 50%. This reaction produced (1R,    4S)-1-amino-4-(hydroxymethyl)-2-cyclopentene.-   3.1.1.3 11 mg of racemic    cis-1-amino-4-(hydroxymethyl)-2-cyclopentene were stirred with 1 ml    of methyl tert-butyl ether, 0.06 ml of tributyrin (glyceryl    tributyrate) and 20 U of Novozym 435 (immob. lipase from Candida    antarctica) at room temperature. After 3 days, enantiomerically    pure, according to HPLC, (1R,    4S)-1-amino-4-(hydroxymethyl)-2-cyclopentene was obtained in 43%    yield.-   3.1.1.4 11 mg of racemic    cis-1-amino-4-(hydroxymethyl)-2-cyclopentene were stirred with 1 ml    of methyl tert-butyl ether. 0.02 ml of 6-caprolactone and 20 U of    Novozym 435 (immob. lipase from Candida antarctica) at room    temperature. After 4 days, (1R,    4S)-1-amino-4-(hydroxymethyl)-2-cyclopentene with 87% ee was    obtained in 49% yield (HPLC).-   3.1.1.5 100 mg of racemic    cis-1-amino-4-(hydroxymethyl)-2-cyclopentene were stirred with 1 ml    of hexane, 0.3 ml of tributyrin and 20 U of Novozym 435 (immob.    lipase from Candida antarctica) at room temperature. After 1 week,    (1R, 4S)-1-amino-4-(hydroxymethyl)-2-cyclopentene with 77% ee was    obtained in 28% yield (HPLC).-   3.1.1.6 100 mg of racemic    cis-1-amino-4-(hydroxymethyl)-2-cyclopentene were stirred with 1 ml    of tert-butanol, 0.3 ml of tributyrin and 20 U of Novozym 435    (immob. lipase from Candida antarctica) at 30° C. After 1 week, (1R,    4S)-1-amino-4-(hydroxymethyl)-2-cyclopentene with 78% ee was    obtained in 15% yield (HPLC).-   3.1.1.7 11 mg of racemic    cis-1-amino-4-(hydroxymethyl)-2-cyclopentene were stirred with 1 ml    of methyl tert-butyl ether, 0.2 mmol of methyl caproate and 20 U of    Novozym 435 (immob. lipase from Candida antarctica) at room    temperature. After 4 days (1R,    4S)-1-amino-4-(hydroxymethyl)-2-cyclopentene with 68% ee was    obtained in 52% yield (HPLC).-   3.1.1.8 11 mg of racemic    cis-1-amino-4-(hydroxymethyl)-2-cyclopentene were stirred with 1 ml    of methyl tert-butyl ether, 0.2 mmol of glycol dibutyrate and 40 U    of Novozym 435 (immob. lipase from Candida antarctica) at room    temperature. After 4 days, (1R,    4S)-1-amino-4-(hydroxymethyl)-2-cyclopentene with 89% ee was    obtained in 31% yield (HPLC).-   3.1.1.9 11 mg of racemic    cis-1-amino-4-(hydroxymethyl)-2-cyclopentene were stirred with 1 ml    of methyl tert-butyl ether, 0.2 mmol of diethyl fumarate and 40 U of    Novozym 435 (immob. lipase from Candida antarctica) at room    temperature. After 4 days, (1R,    4S)-1-amino-4-(hydroxymethyl)-2-cyclopentene with 86% ee was    obtained in 36% yield (HPLC).-   3.1.1.10 11 mg of racemic    cis-1-amino-4-(hydroxymethyl)-2-cyclopentene were stirred with 1 ml    of methyl tert-butyl ether, 0.2 mmol of diethyl malonate and 40 U of    Novozym 435 (immob. lipase from Candida antarctica) at room    temperature. After 4 days, (1R,    4S)-1-amino-4-(hydroxymethyl)-2-cyclopentene with 86% ee was    obtained in 21% yield (HPLC).-   3.1.1.11 11 mg of racemic    cis-1-amino-4-(hydroxymethyl)-2-cyclopentene were stirred with 1 ml    of diisopropyl ether, 0.2 mmol of tributyrin and 40 U of Novozym 435    (immob. lipase from Candida antarctica) at room temperature. After 4    days, enantiomerically pure (1R,    4S)-1-amino-4-(hydroxymethyl)-2-cyclopentene was obtained in 15%    yield (HPLC).-   3.1.1.12 11 mg of racemic    cis-1-amino-4-(hydroxymethyl)-2-cyclopentene were stirred with 1 ml    of diisopropyl ether, 0.2 mmol of diethyl fumarate and 40 U of    Novozym 435 (immob. lipase from Candida antarctica) at room    temperature. After 4 days, (1R,    4S)-1-amino-4-(hydroxymethyl)-2-cyclopentene with 88% ee was    obtained in 24% yield (HPLC).-   3.1.1.13 11 mg of racemic    cis-1-amino-4-(hydroxymethyl)-2-cyclopentene were stirred with 1 ml    of diisopropyl ether, 0.2 mmol of diethyl malonate and 40 U of    Novozym 435 (immob. lipase from Candida antarctica) at room    temperature. After 4 days, (1R,    4S)-1-amino-4-(hydroxymethyl)-2-cyclopentene with 82% ee was    obtained in 14% yield (HPLC).-   3.1.1.14 11 mg of racemic    cis-1-amino-4-(hydroxymethyl)-2-cyclopentene were stirred with 1 ml    of diisopropyl ether, 0.2 mmol of diethyl diglycolate and 40 U of    Novozym 435 (immob. lipase from Candida antarctica) at room    temperature. After 4 days, (1R,    4S)-1-amino-4-(hydroxymethyl)-2-cyclopentene with 88% ee was    obtained in 7% yield (HPLC).-   3.1.1.15 11 mg of racemic    cis-1-amino-4-(hydroxymethyl)-2-cyclopentene were stirred with 1 ml    of dibutyl ether, 0.2 mmol of tributyrin and 40 U of Novozym 435    (immobilized lipase from Candida antarctica) at room temperature.    After 4 days, (1R, 4S)-1-amino-4-(hydroxymethyl)-2-cyclopentene with    95% ee was obtained in 13% yield (HPLC).-   3.1.1.16 11 mg of racemic    cis-1-amino-4-(hydroxymethyl)-2-cyclopentene were stirred with 1 ml    of pyridine, 0.02 ml of ethyl 2-methoxyacetate and 20 mg of lipase    AK (lipase from Pseudomonas fluorescens) at room temperature. After    4 days, (1R, 4S)-1-amino-4-(hydroxymethyl)-2-cyclopentene with 84%    ee was obtained in 18% yield (HPLC).-   3.1.1.17 11 mg of racemic    cis-1-amino-4-(hydroxymethyl)-2-cyclopentene were stirred with 1 ml    of methyl tert-butyl ether, 0.2 mmol of ethyl cyanoacetate and 10 mg    of lipase PS (lipase from Pseudomonas cepacia) at room temperature.    After 4 days, (1R, 4S)-1-amino-4-(hydroxymethyl)-2-cyclopentene with    67% ee was obtained in 40% yield (HPLC).-   3.1.1.18 11 mg of racemic    cis-1-amino-4-(hydroxymethyl)-2-cyclopentene were stirred with 1 ml    of methyl tert-butyl ether, 0.2 mmol of diethyl fumarate and 10 mg    of lipase PS (lipase from Pseudomonas cepacia) at room temperature.    After 4 days, (1R, 4S)-1-amino-4-(hydroxymethyl)-2-cyclopentene with    86% ee was obtained in 18% yield (HPLC).

3.1.2 Preparation of (1R, 4S)-1-amino-4-(hydroxy-methyl)-2-cyclopenteneusing proteases

-   3.1.2.1 11 mg of racemic    cis-1-amino-4-(hydroxymethyl)-2-cyclopentene were stirred with 1 ml    of 2-methyl-2-butanol, 0.2 mmol of diethyl maleate and 40 mg of    Alcalase (protease from Bacillus licheniformis) at room temperature.    After 4 days, (1R, 4S)-1-amino-4-(hydroxymethyl)-2-cyclopentene with    28% ee was obtained in 39% yield (HPLC).-   3.1.2.2 11 mg of racemic    cis-1-amino-4-(hydroxymethyl)-2-cyclopentene were stirred with 1 ml    of 2-methyl-2-butanol, 0.2 mmol of diethyl fumarate and 40 mg of    Savinase (protease from Bacillus sp.) at room temperature. After 4    days, (1R, 4S)-1-amino-4-(hydroxymethyl)-2-cyclopentene with 32% ee    was obtained in 42% yield (HPLC).-   3.1.2.3 11 mg of racemic    cis-1-amino-4-(hydroxymethyl)-2-cyclopentene were stirred with 1 ml    of 2-methyl-2-butanol, 0.06 ml of tributyrin and 20 mg of Savinase    (protease from Bacillus sp.) at room temperature. After 4 days, (1R,    4S)-1-amino-4-(hydroxymethyl)-2-cyclopentene with 22% ee was    obtained in 39% yield (HPLC)-   3.1.2.4 11 mg of racemic    cis-1-amino-4-(hydroxymethyl)-2-cyclopentene were stirred with 1 ml    of 2-methyl-2-butanol, 0.06 ml of tributyrin and 20 mg of subtilisin    (protease from Bacillus licheniformis) at room temperature. After 4    days, (1R, 4S)-1-amino-4-(hydroxymethyl)-2-cyclopentene with 23% ee    was obtained in 36% yield (HPLC).

3.1.3 Preparation of (1S, 4R)-1-amino-4-(hydroxy methyl)-2-cyclopenteneusing proteases

-   3.1.3.1 11 mg of racemic    cis-1-amino-4-(hydroxymethyl)-2-cyclopentene were stirred with 1 ml    of hexane, 0.06 ml of tributyrin and 120 U of Savinase (protease    from Bacillus sp.) at room temperature. After 3–6 days, (1S,    4R)-1-amino-4-(hydroxymethyl)-2-cyclopentene with 44% ee was    obtained in 46% yield (HPLC).-   3.1.3.2 11 mg of racemic    cis-1-amino-4-(hydroxymethyl)-2-cyclopentene were stirred with 1 ml    of hexane, 0.06 ml of tributyrin and 20 mg of Alcalase (protease    from Bacillus licheniformis) at room temperature. After 3–6 days,    (1S, 4R)-1-amino-4-(hydroxymethyl)-2-cyclopentene with 44% ee was    obtained in 35% yield (HPLC).

3.1.4 Preparation of (1S, 4R)-1-amino-4-(hydroxymethyl)-2-cyclopenteneusing lipases

-   3.1.4.1 11 mg of racemic    cis-1-amino-4-(hydroxymethyl)-2-cyclopentene were stirred with 1 ml    of 2-methyl-2-butanol, 0.03 ml of ethyl butyrate and 20 mg of    Newlase F (lipase from Rhizopus niveus) at room temperature. After 1    week, (1S, 4R)-1-amino-4-(hydroxymethyl)-2-cyclopentene with 39% ee    was obtained in 37% yield (HPLC).-   3.1.4.2 11 mg of racemic    cis-1-amino-4-(hydroxymethyl)-2-cyclopentene were stirred with 1 ml    of pyridine, 0.06 ml of tributyrin and 20 mg of lipase AK (lipase    from Pseudomonas fluorescens) at room temperature. After 1 week,    (1S, 4R)-1-amino-4-(hydroxymethyl)-2-cyclopentene with 30% ee was    obtained in 10% yield (HPLC).-   3.1.4.3 11 mg of racemic    cis-1-amino-4-(hydroxymethyl)-2-cyclopentene were stirred with 1 ml    of 2-methyl-2-butanol, 0.06 ml of tributyrin and 20 mg of lipase AY    (lipase from Candida rugosa) at room temperature. After 1 week, (1S,    4R)-1-amino-4-(hydroxymethyl)-2-cyclopentene with 32% ee was    obtained in 13% yield (HPLC).-   3.1.4.4 11 mg of racemic    cis-1-amino-4-(hydroxymethyl)-2-cyclopentene were stirred with 1 ml    of methyl t-butyl ether, 0.06 ml of tributyrin and 20 mg of lipase    PS-CI (immobilized lipase from Pseudomonas cepacia) at room    temperature. After 1 week, (1S,    4R)-1-amino-4-(hydroxymethyl)-2-cyclopentene with 29% ee was    obtained in 16% yield (HPLC).-   3.1.4.5 11 mg of racemic    cis-1-amino-4-(hydroxymethyl)-2-cyclopentene were stirred with 1 ml    of methyl t-butyl ether, 0.06 ml of tributyrin and 20 mg of lipase    PS (lipase from Pseudomonas cepacia) at room temperature. After 1    week, (1S, 4R)-1-amino-4-(hydroxymethyl)-2-cyclopentene with 24% ee    was obtained in 22% yield (HPLC).

3.2 Racemate resolution using D-(−)-tartaric acid

-   3.2.1 A mixture of 8 g (70.6 mmol) of racemic    1-amino-4-(hydroxymethyl)-2-cyclopentene and 10.6 g (70.6 mmol) of    D-(−)-tartaric acid in 186 g of methanol were dissolved at the    reflux temperature. The mixture was then cooled to 20° C. over 2 h.    At 43° C., seed crystals of the pure (1R,    4S)-1-amino-4-(hydroxymethyl)-2-cyclopentene D-hydrogentartrate were    added. The crystallized product was filtered off and dried. Yield:    8.49 g (45.6% based on racemic starting material) of (1R,    4S)-1-amino-4-(hydroxymethyl)-2-cyclopentene D-hydrogentartrate, ee    value: 91.1%. For purification, 8.49 g (32.25 mmol) of the    hydrogentartrate were suspended in 30 ml of methanol, and 2    equivalents of 30% sodium methoxide were added. The sodium tartrate    was filtered off and the methanol was distilled off.    -   The residue was taken up in 35 ml of pentanol. Then, at 55° C.,        1.5 g of HCl were introduced, and the solution was slowly        cooled. At 40° C., the solution was seeded with (1R,        4S)-1-amino-4-(hydroxymethyl)-2-cyclopentene hydrochloride. 45        ml of acetone were then metered in, and the suspension was        slowly cooled to 0° C. and filtered, and the residue was dried.        3.91 g of (1R, 4S)-1-amino-4-(hydroxymethyl)-2-cyclopentene        hydrochloride having an ee value of >98% were obtained,        corresponding to a yield, based on racemic (1R,        4S)-1-amino-4-(hydroxymethyl)-2-cyclopentene used, of 37%.-   3.2.2 A mixture of 64 g of racemic    1-amino-4-(hydroxymethyl)-2-cyclopentene (0.5 mol) and 75.2 g of    D-(−)-tartaric acid in 1330 g of methanol was dissolved at the    reflux temperature and then cooled to 20° C. over 2 h. At 43° C.,    seed crystals of the pure 1R, 4S-enantiomer were added. The    crystallized product was filtered off and dried. Yield: 63.2 g    (48.0% based on racemic l-amino-4-(hydroxymethyl)-2-cyclopentene) of    (1R, 4S)-1-amino-4-(hydroxymethyl)-2-cyclopentene hydrogentartrate,    ee value: 91.1%. The ee value in the mother liquor was 76.0%.

3.2.3 Recrystallization of 1R, 4S-(4-amino-2-cyclopenten-1-yl)methanolD-hydrogentartrate

-   -   61.84 g of 1R, 4S-(4-amino-2-cyclopenten-1-yl)-methanol        D-hydrogentartrate (0.235 mol, ee value 91.1%) were dissolved in        752 g of methanol under reflux. The solution was cooled to        20° C. within 90 min, then the product was filtered off and        washed with 64 g of cold methanol. Drying gave 54.56 g of 1R,        4S-(4-amino-2-cyclopenten-1-yl)-methanol D-hydrogentartrate were        obtained, ee value 99.4% (yield 88.2%, 42.3% based on racemic        1-amino-4-(hydroxymethyl)-2-cyclopentene). This was used tel        quel in the chloropurine synthesis.

-   3.2.4 Following the procedure of Example 3.2.2, but using 223 g of    methanol and seeding at 50° C., the racemate was separated. The    yield was 7.98 g (42.9% based on racemic (1R,    4S)-1-amino-4-(hydroxymethyl)-2-cyclopentene used).

3.3 Racemate resolution using L-(+)-tartaric acid

-   3.3.1 A mixture of 8 g (70.6 mmol) of racemic    1-amino-4-(hydroxymethyl)-2-cyclopentene and 10.6 g (70.6 mmol) of    L-(+)-tartaric acid in 186 g of methanol were dissolved at the    reflux temperature. The mixture was then cooled to 20° C. over 2 h.    At 43° C., seed crystals of the pure (1S,    4R)-1-amino-4-(hydroxymethyl)-2-cyclopentene L-hydrogentartrate were    added. The crystallized (1S,    4R)-1-amino-4-(hydroxymethyl)-2-cyclopentene L-hydrogentartrate was    filtered off and dried. (ee value: 91.1%). 14 g of 30% methanolic    sodium methoxide were added to the mother liquor, then the methanol    was evaporated. The residue was taken up in 35 ml of isobutanol, and    the insoluble sodium tartrate was filtered off. At 55° C., 2 g of    gaseous HCl were introduced into the filtrate. 38 ml of acetone were    then added, and the mixture was left to cool to 10° C. over the    course of 1 h. After 1 h, the (1R,    4S)-1-amino-4-(hydroxymethyl)-2-cyclopentene hydrochloride was    filtered off with suction and washed with 8 ml of acetone. Drying    under reduced pressure gave the (1R,    4S)-1-amino-4-(hydroxymethyl)-2-cyclopentene hydrochloride in a    yield of 34 g, 31.6% based on racemic    1-amino-4-(hydroxymethyl)-2-cyclopentene with an ee value of >98%.

Example 4 Preparation of (1R, 4S)-amino-4-(hydroxymethyl)-2-cyclopentenehydrochloride 4.1 Reduction of (−)-2-azabicyclo[2.2.1]hept-5-en-3-one

-   -   A 2 l autoclave (stainless steel type V4A) rendered inert with        N₂, was charged with 61.4 g of sodium borohydride 97.5% (1.623        mol), 70.2 g of lithium chloride 98.5% (1.656 mol), 13.2 g of        Celite and 1410 g of tetrahydrofuran. The autoclave was closed        and heated to an internal temperature of 130° C. and the        contents stirred for 4.5 hours at this temperature (max. 8.0        bar).    -   After the autoclave had been cooled to about 60° C., the sodium        salts insoluble in tetrahydrofuran (NaCl, NaBH₄) were filtered        off. These were washed with 353 g of tetrahydrofuran, and the        combined filtrates were reduced to about half in a stirred 1 l        glass vessel by distillation at atmospheric pressure (distillate        1: about 710 g of tetrahydrofuran). Further distillation,        alternating with the portion-wise addition of a total of 936 g        of dioxane then completed the solvent exchange (distillate 2:        about 1289 g of tetrahydrofuran/dioxane).    -   The LiBH₄ suspension was cooled to about 60° C., and 56.7 g of        (−)-2-azabicyclo[2.2.1]hept-5-en-3-one (97.5%) were added.    -   Starting at about 60° C., 132.5 g of methanol were metered in in        exactly one hour at a rate such that a temperature range of        58–62° C. was maintained. The mixture was then allowed to react        for a further hour at 60° C. A further 397.0 g of methanol were        then added (sample comprises an analytical yield of 70.5%), and        the contents of the stirred vessel were cooled to 0° C. At this        temperature, 90.0 g of HCl were introduced into the reaction        mixture (slightly exothermic) and stirring was continued for a        further hour at about 0° C. Distillation at atmospheric pressure        (up to a head temperature of 75° C.) removed the low-boiling        fractions (methanol, borate) and about 70% of the dioxane        (distillate 3: about 1093 g). Distillation under reduced        pressure (about 30 mbar), alternating with the portionwise        addition of a total of 282 g of 1-pentanol then completed the        solvent exchange (distillate 4: about 240 g of        dioxane/pentanol).

After a further 302 g of 1-pentanol had been added, the mixture wasstirred for 1 hour at 50° C., and precipitated salts, about 39 g moistweight, were filtered off and washed with 200 g of 1-pentanol. Thecombined filtrates were reduced by redistillation under reduced pressure(about 20 mbar) (distillate 5: 235 g of 1-pentanol). Then, at about 50°C., 236 g of acetone were metered in, and the reaction mixture wasseeded with a few crystals of (1R,4S)-amino-4-(hydroxymethyl)-2-cyclopentene. The mixture was cooled to 5°C. over the course of 1 hour, and crystallization was completed bystirring the mixture for a further 6 h at 5° C.

-   -   The crystals were filtered off, washed with 63 g of acetone and        dried at a max. 50° C. in a vacuum drying cabinet (10 mbar).        This gave 83.5 g of crude product* (content: 56.5%).    -   This corresponded to a yield of 61.4% based on        (−)-2-azabicyclo[2.2.1]hept-5-en-3-one used.

4.2 Reduction of (±)-2-azabicyclo[2.2.1]hept-5-en-3-one

-   -   A 2 l autoclave (stainless steel type V4A) rendered inert with        N₂, was charged with 41.56 g of sodium borohydride 97.5% (1.071        mol), 51.48 g of lithium chloride 98.5% (1.196 mol), 9.30 g of        Celite and 955.0 g of tetrahydrofuran. The autoclave was closed        and heated to an internal temperature of 130° C. and the        contents stirred for 6 hours at this temperature (max. 6.3 bar).    -   After the autoclave had been cooled to about 60° C., the sodium        salts insoluble in tetrahydrofuran (NaCl, NaBH₄) were filtered        off. These were washed with 239.0 g of tetrahydrofuran, and the        combined filtrates were reduced to about half in a stirred 1 l        glass vessel by distillation at atmospheric pressure.        (distillate 1: about 590 g of THF). Further distillation,        alternating with the portionwise addition of a total of 661.0 g        of dioxane then completed the solvent exchange (distillate 2:        about 685 g of tetrahydrofuran/dioxane).    -   The LiBH₄ suspension was cooled to about 60° C., and 36.0 g of        2-azabicyclo[2.2.1]hept-5-en-3-one (97.5%) were added.    -   Starting at about 60° C., 77.6 g of methanol were metered in in        exactly one hour at a rate such that a temperature range of        58–62° C. was maintained. The mixture was then allowed to react        for a further hour at 60° C. A further 233.0 g of methanol were        then added, and the contents of the stirred vessel were cooled        to 0° C. At this temperature, 52.9 g of HCl were introduced into        the reaction mixture (slightly exothermic) and stirring was        continued for a further hour at about 0° C. Distillation at        atmospheric pressure (up to a head temperature of 75° C.)        removed the low-boiling fractions (methanol, borate) and about        70% of the dioxane (distillate 3: about 700 g). Distillation        under reduced pressure (about 30 mmol), alternating with the        portionwise addition of a total of 169.4 g of 1-pentanol then        completed the solvent exchange (distillate 4: about 183 g of        dioxane/pentanol). After a further 127.1 g of 1-pentanol had        been added, the mixture was stirred for 1 hour at 50° C., and        precipitated salts, about 41 g moist weight, were filtered off        and washed with 63.5 g of 1-pentanol. The combined filtrates        were reduced by redistillation under reduced pressure (about 20        mbar) (distillate 5: 235 g of 1-pentanol). Then, at about 50°        C., 238.0 g of acetone were metered in, and the reaction mixture        was seeded with a few crystals of aminoalcohol hydrochloride        salt. The mixture was cooled to 5° C. over the course of one        hour, and crystallization was completed by stirring the mixture        for a further 6 hours at 5° C.    -   The crystals were filtered off, washed with 61.0 g of acetone        and dried at a max. 50° C. in a vacuum drying cabinet (10 mbar).        This gave 50.0 g of crude product (content: about 50% of        aminoalcohol hydrochloride salt).    -   This corresponded to a yield of 52.0% based on        2-azabicyclo[2.2.1]hept-5-en-3-one used.

Example 5 Preparation of acylated aminoalcohols 5.1 Preparation of (1R,4S)-N-BOC-1-amino-4-(hydroxy-methyl)-2-cyclopentene(BOC=tert-butoxycarbonyl)

-   -   75 g of a solution of (1R,        4S)-1-amino-4-hydroxy-methyl-2-cyclopentene were adjusted to pH        8 using 30% strength NaOH, and 6 g of NaHCO₃ were added to the        mixture. The mixture was heated to 52° C. Whilst stirring the        mixture thoroughly, 60 ml of diisopropyl ether were added        thereto and then, over the course of 2 h, a solution of 11.12 g        of BOC anhydride in 18.2 ml of diisopropyl ether were metered        in. The mixture was filtered over Celite, and the phases were        separated. The aqueous phase was extracted with 65 ml of        diisopropyl ether. The combined organic phases were washed with        45 ml of water, then evaporated to 37.5 g and heated to 50° C.        31 ml of n-hexane were added dropwise to the solution. After the        mixture had been slowly cooled to 0° C. (2 h), the title        compound was filtered, washed with 12 ml of n-hexane/diisopropyl        ether 1/1 and dried. This gave 6.75 g of product. The yield was        71%.

5.2 Preparation of (1R,4S)-N-acetyl-1-amino-4-(hydroxy-methyl)-2-cyclopentene

-   -   25 g (1R, 4S)-1-amino-4-(hydroxymethyl)-2-cyclopentene        hydrochloride were dissolved in 182 ml of acetic anhydride, and        at 0° C., a solution of 18.25 g of triethylamine in 60 ml of        acetic anhydride were added thereto. The mixture was stirred at        80° C. for 3 h, then cooled to room temperature. The        triethylamine hydrochloride was filtered off and washed with 120        ml of n-hexane. The filtrate was evaporated. 300 ml of toluene        were added to the residue, and the mixture was stirred at room        temperature in the presence of 5.2 g of activated carbon and 13        g of Celite for 20 min. The mixture was then filtered, and the        filter cake was washed (3×40 ml of toluene), and the solvent was        completely evaporated. 180 ml of methanol and 15.5 g of K₂CO₃        were added to the residue, and the mixture was stirred at room        temperature for 10 h. The suspension was filtered off and the        filtrate evaporated. The residue was suspended in 750 ml of        isopropyl acetate and boiled in the presence of 0.5 g of        activated carbon to reflux for 1.5 h. Following filtration of        the activated carbon (70–80° C.), the filtrate was cooled at        0° C. overnight. The title compound was filtered, washed with 80        ml of cold isopropyl acetate and dried under reduced pressure to        give 17.2 g of product. The yield was 66%.

5.3 Preparation of (1R,4S)-N-butyryl-1-amino-4-(hydroxy-methyl)-2-cyclopentene

-   -   34.7 g of (1R, 4S)-1-amino-4-hydroxymethyl-2-cyclo-pentene        hydrochloride and 2 g of N,N-4-dimethyl-aminopyridine were        dissolved in 600 ml of methylene chloride. The solution was        cooled to 0° C. 52 g of triethylamine were then added dropwise        (5 min). The mixture was stirred for a further 30 min. At 0° C.,        a solution of 35.2 g of butyryl chloride in 60 ml of methylene        chloride was metered into the mixture over the course of 1 h.        The mixture was stirred for a further 1.5 h at between 0 and 20°        C., and then 600 ml of water were added thereto. Following phase        separation, the aqueous phase was extracted with 600 ml of        methylene chloride. The combined organic phases were washed        3×500 ml of 10% strength NaOH, then completely evaporated. The        dried solid was dissolved in 120 ml of methanol. 5 g of K₂CO₃        were added to the solution, and the mixture was stirred for a        further 2 h at room temperature. The inorganic salts were        filtered off and washed with 20 ml of methanol. The filtrate was        neutralized with 2N HCl. The suspension was filtered off, and        the filter cake was washed with 20 ml of methanol. The filtrate        was completely evaporated. The solid residue was dried and        crystallized in 150 ml of toluene to give 28.5 g of the title        compound. The yield was 67%.

Example 6 Preparation of[4(R)-(2-amino-6-chloro-purine-9-yl)cyclopent-2-ene-1(S)-yl]methanol 6.1Preparation of[4(R)-(2-amino-6-chloropurine-9-yl)-cyclopent-2-ene-l(S)-yl]methanolstarting from 1R, 4S- (4-amino-2-cyclopenten-1-yl)methanolD-hydrogentartrate

-   -   47.4 g of 1R, 4S-(4-amino-2-cyclopenten-1-yl)methanol        D-hydrogentartrate (0.18 mol, ee >98%) in 200 ml of ethanol were        introduced initially. At room temperature, 54.6 g of NaHCO₃        (0.65 mol) and 37.3 g (0.18 mol) of        N-(2-amino-4,6-dichloro-4-pyrimidyl)-formamide were added,        boiled for 9 h under reflux and then cooled to room temperature.        The salts were filtered off and then washed with 50 ml of        ethanol. The filtrate was concentrated to 280 g on a rotary        evaporator. 18.4 g of HCl gas were introduced into the resulting        solution at T<25° C., then 95.5 g (0.9 mol) of trimethyl        orthoformate were added, and the whole was heated to 40° C. (10        min). At this temperature, the mixture was seeded with        chloro-purine hydrochloride. After 2 h at 42° C., the product        crystallized out. The suspension was cooled to 15° C. The        product was filtered and then washed with 3×50 ml of ethanol,        then dried at 50° C. under reduced pressure. The yield was 41.9        g (75.8%). Beige powder, content (HPLC): 95.0%.

6.2 Preparation of(4(R)-(2-amino-6-chloropurine-9-yl)-cyclopent-2-ene-1(S)-yl]methanolStarting from (−)-2-azabicyclo[2.2.1]hept-5-en-3-one

-   -   A 2 l autoclave (stainless steel type V4A) rendered inert with        N₂, was charged with 61.4 g of sodium borohydride 97.5% (1.623        mol), 70.2 g of lithium chloride 98.5% (1.656 mol), 13.2 g of        Celite and 1410 g of tetrahydrofuran. The autoclave was closed        and heated to an internal temperature of 130° C. and the        contents stirred for 4.5 hours at this temperature (max. 8.0        bar). After the autoclave had been cooled to about 60° C., the        sodium salts insoluble in tetrahydrofuran (NaCl, NaBH₄) were        filtered off. These were washed with 353 g of tetrahydrofuran,        and the combined filtrates were reduced to about half in a        stirred 1 l glass vessel by distillation at atmospheric pressure        (distillate 1: about 710 g of tetrahydrofuran). Further        distillation, alternating with the portionwise addition of a        total of 936 g of dioxane then completed the solvent exchange        (distillate 2: about 1289 g of tetrahydrofuran/dioxane).    -   The LiBH₄ suspension was cooled to about 60° C., and 56.7 g of        (−)-2-azabicyclo[2.2.1]hept-5-en-3-one (97.5%/0.507 mol) were        added.    -   Starting at about 60° C., 132.5 g of methanol were metered in in        exactly one hour at a rate such that a temperature range of        58–62° C. was maintained. The mixture was then allowed to react        for a further hour at 60° C. A further 397.0 g of methanol were        then added (sample comprises an analytical yield of 70.5%), and        the contents of the stirred vessel were cooled to 0° C. At this        temperature, 90.0 g of HCl were introduced into the reaction        mixture (slightly exothermic) and stirring was continued for a        further hour at about 0° C. The solution was evaporated on a        rotary evaporator at 50° C. under reduced pressure, 200 ml of        methanol were added and the methanol was removed again        (filtration with suction of the methyl borate). The procedure        was repeated using a further 200 ml of methanol. 250 ml of        ethanol were added to the oil obtained (253.4 g comprise 3.16%        of amino-alcohol; this corresponded to 0.360 mol), and the        mixture was poured into a 1 l double-jacketed stirred vessel. At        room temperature, 72.6 g of NaHCO₃ (0.86 mol) and 74.6 g (0.360        mol) of N-(2-amino-4,6-dichloro-4-pyrimidyl)formamide were        added, the mixture was refluxed for 9 h and cooled to room        temperature, and the salts were filtered off and then washed        with 100 ml of ethanol. The filtrate on the rotary evaporator        was concentrated to 560 g. 63.4 g of HCl gas were introduced        into the resulting solution at T<25° C., then 191.0 g (1.80 mol)        of trimethyl orthoformate were added, and the mixture was heated        to 40° C. (10 min). At this temperature, the mixture was seeded        with chloropurine hydrochloride, and left to crystallize for 2 h        at 42° C. The suspension was cooled to 15° C. The product was        filtered and then washed with 3×50 ml of ethanol, then dried at        50° C. under reduced pressure. The yield was 66.0 g (59.7%).        Beige powder, content (HPLC): 89.3% This corresponded to a yield        of 42.4% based on the Vince lactam used.

1. A process for preparing (1S,4R)— or(1R,4S)-1-amino-4-(hydroxymethyl)-2-cyclopentene of the formula:

or a salts thereof or a(1S,4R)— or(1R,4S)-1-amino-4-(hydroxymethyl)-2-cyclopentene derivatives of thegeneral formula:

or a salts thereof, in which X and Y are identical or different andproviding that X and Y are an acyl group or H, with the exception ofX=Y=H, comprising resolving the racemate of the formula

into its separate enantiomers by chemical means using D-(−) orL-(+)-tartaric acid.